Justin C. McArthur - US grants

neurotropic virus;

This Research Center will investigate the clinical manifestations, cellular pathology, and pathogenetic mechanisms of the neurological complications of HIV infections in humans. In addition, animal models will be developed to provide insights into the pathogenesis f neural lesions. Cohorts of persons infected by different routes, including gay men, intravenous drug users, and infants of HIV- positive mothers, will be studied prospectively to determine the frequency, spectrum and course of central and peripheral nervous system complications. This longitudinal data along with cross- sectional clinical data on patients with AIDS will provide the base for morphological, imaging, and immunological studies. Cellular pathology will be defined with a variety of morphological methods with emphasis on delineating the peripheral nerve abnormalities, the involvement of the dorsal root and autonomic ganglia, and the cellular pathology of the vacuolar myelopathy and HIV encephalopathy. This encephalopathy will be studied during life using quantitative MRI and single photon emission computed tomography (SPECT) methods and post-mortem with morphometric analysis. Selective or diffuse neuronal loss and the basis of the diffuse myelin pallor will be studied. The phenotype of inflammatory cells, their state of activation and presence and localization of cytokines in nervous system tissue will be correlated with localization of viral antigens and RNA; conversely, the effect of HIV infection on macrophage function and monokine production will be examined. Transgenic mice containing specific and the possible role of gene products in nervous system pathology. The pathogenesis of the neurological involvement with feline immunodeficiency lentivirus will be investigated as a practical animal model for the neurological complications of HIV infection.

Infection with human immunodeficiency virus (HIV) is associated with the development of distinct neurological disorders, including dementia, myelopathy, and sensory neuropathy. Usually occurring in advanced HIV infection, the clinical features and temporal progression of these disorders remains incompletely characterized. Unanswered issues include the discordance between the clinical expression of dementia and the absence of HIV-related neuropathological changes; the timing of development of HIV-related neuropathological change with respect to systemic disease and immunodeficiency; the influence of antiretroviral therapy on neuropathological abnormalities; and the characterization of the sensory neuropathies in AIDS. The proposed studies will test four hypotheses: First, that quantitative differences in neuronal loss, astrocyte and microglial/macrophage proliferation, and expression of viral antigens in the brain determine the clinical course of HIV dementia. Second, despite entry of HIV into the brain relatively early in infection, the neuropathological changes associated with productive HIV infection develop only with advanced immune deficiency. Third, that specific antiretroviral therapies attenuate the neuropathological changes in dementia and myelopathy. Fourth, that the clinical expression of sensory neuropathy is related to changes in unmyelinated fiber densities and is provoked by certain antiretrovirals and nutritional deficiencies. By using well-characterized patients with advanced HIV infection, our studies will use state of the art stereological techniques to determine regional distribution of neuronal, astrocyte, and microglial numbers, and correlate these findings with patterns of neurocognitive decline, clinical features, and temporal progression of dementia and myelopathy. In patients with sensory neuropathy, the neuropathic pain will be characterized and related to changes in the structure and function of unmyelinated nerve fiber. Skin biopsy will be used to measure the degree of distal nerve fiber loss and will be validated by the study of nerve obtained by biopsy and autopsy. The studies will correlate the clinical expression of HIV-associated neurological disease with neuropathological abnormalities in brain, spinal cord, and peripheral nerve. The information from these projects will be applicable to the exploration of pathogenetic mechanisms and the rational design of therapies.

The purpose of this project was to determine the efficacy of Ara-C comparing intravenous administration to intrathecal administration in the treatment of PML along with a comparison arm receiving maximized antiretroviral therapy alone. We only had one patient active in this clinical trial during the above time period. This patient was receiving intrathecal Ara-C. The patient tolerated the study treatment well. Despite this, the PML continued to progress and the patient discontinued the study at week 6 due to the PML progression. He died ten days later due to PML progression. The previous five patients all died as well due to PML progression and none survived a sufficient length of time to complete the trial (24 weeks). We recruited 6 patients total at Hopkins for this trial. Nationwide, there were 62 patients enrolled in the study. The Protocol Safety Monitoring Board (PSMB) for the Neurological AIDS Research Consortium met on 7/2/96 to review the results of this trial. No statistical differences were noted in the survival times between the three treatment arms nor in the two Ara-C arms combined (IV plus intrathecal) vs non Ara-C. The PSMB determined that there was only a very slight chance of showing a benefit of Ara-C treatment and recommended not enrolling additional subjects as the Ara-C treatment had not been found to be effective in treating PML. The original recruitment goal was 90 subjects. There were no major safety issues regarding the use of the study medication. The Ara-C was well tolerated by the study subjects.

The purpose of this study is to determine the safety, tolerability and efficacy of pain relief of recombinant human nerve growth factor (rhNGF) for HIV-associated sensory neuropathy. Five patients were enrolled and active in this clinical trial during the above time period (recruitment started during 8/96). Patients can be randomized to either a low dose rhNGF, a high dose rhNGF or placebo. All five patients have tolerated the study medication well. Two of the patients have reported a benefit in their neuropathy while the other three patients have reported no change. Since 11/30/96, the recruitment for this study continues to grow. We now have 7 patients active in this study and more in the screening process. Nationwide, there are now 147 patients enrolled among 15 sites. At the current rate, the national recruitment goal of 180 participants will be reached by approximately 2/28/97. Due to the rapid accrual rate and to statistical reasons, the study is currently being amended to: 1) increase the number of participants in this study to 260 or 270 and 2) to provide a 48 week open-label phase of this study that would be open to all participants who successfully completed the initial double-blind phase of the study. Participants will either receive low dose or high dose rhNGF during this phase of the trial. No interim analysis has been conducted on the data collected thus far at this point in time.

HIV dementia remains an important manifestation of AIDS, developing in up to 15%. Despite highly active anti-retroviral therapy (HAART), the prosect that the brain might remain a sanctuary for HIV replication is real, and of great relevance for the effective long-term suppression of HIV infection. The Research Center will extend the observations that we have made during the last decade. The Research Center will refocus its questions in the context of the recent advances which have been made in our understanding of the biology of HIV infection and the therapy of HIV infection. The Research Center will investigate the mechanisms of neuronal damage and death. CNS, therapeutic responses to HAART, and the immunopathology and virology of HIV-associated dementia ("AIDS dementia"). HIV seropositive individuals will be studied prospectively to characterize the severity of neurological impairment. Individuals initiating HAART will have serial CSF analyses to study the acquisition of resistance mutations and to relate these to the durability of suppression of CSF HIV levels. The systematic clinical characterization of HIV-infected individuals through the Cores will provide the basis for detailed clinicopathological correlation in autopsy material using a variety of morphological methods, including assessment of the degree and cellular localization of cytokines and chemokines, and the state of activation of tissue macrophages. The mechanisms of monocyte entry into the CNS and regulation of cytokine and chemokine production will be examined in vitro. The importance of biological differences in brain HIV isolates from patients with and without dementia will be examined, with respect to their replicative capacity and ability to induce pro-inflammatory mediators. The role of the bone marrow in the aberrant production and processing of monocytes which potentially leads to increased CNS entry of activated or infected monocyte/macrophages will be explored. Finally, the mechanisms of neuronal injury and death, and the potential neurotoxic effects of viral proteins including gp41, will be examined. These studies will lead to an improved understanding of the pathophysiological mechanisms which lead to HIV dementia, and are likely to stimulate new avenues of therapy for HIV dementia. The studies of CSF viral load and resistance patterns will be directly relevant to the management of patients with established HIV dementia. The studies of CSF viral load and observations should lead to improvement sin the application of anti-retroviral and other therapies directed at the prevention or treatment of HIV dementia.

Antiretroviral agents are currently the only approved therapy for treatment of HIV dementia, but treatment response is frequently unsatisfactory or short-lived, or agents poorly tolerated in doses adequate for CNS penetration. The reason for the incomplete response may be that the pathophysiology of HIV-related cognitive impairment is initiated by the virus, but involves a complicated inflammatory cascade within the brain. Therefore, effective therapy needs to focus on these indirect mechanisms in addition to viral suppression. One hypothesis for the pathophysiology of dementia is that neurotoxic substances are produced by specific interactions between infected macrophages and astrocytes to damage and destroy neurons. In this schema, we are interested in the role of the lipid inflammatory mediator, platelet activating factor (PAF). This is a potent biological mediator that exerts its effects in as variety of cells and tissues and has been detected at high levels in the CSF of immune-suppressed HIV-1 infected patients with CNS dysfunction. Lexipafant is a PAF antagonist with high affinity for the PAF receptor with an excellent safety profile. Currently, controlled clinical trials of Lexipafant are under way in treatment of asthma, pancreatitis, ulcerative colitis and pre-operative ischemia. It has shown to be active via oral route and is well- tolerated in human volunteers using doses up to 750 mg bid. No prior clinical research has been reported with Lexipafant in HIV-infected individuals.

This is a phase II, multicenter, randomized, double-blind, placebo- controlled trial of the safety, tolerability and efficacy of pain relief of lamotrigine for HIV-associated sensory neuropathy. Peripheral neuropathy is a common complication of HIV infection. HIV-associated sensory neuropathy is a common form of neuropathy in advanced HIV infection. Approximately 30% of patients with AIDS develop HIV-associated sensory neuropathy. Symptoms can be painful and can greatly impact on the activities of daily living as well as the quality of life. A direct viral etiology has been postulated as a causative agent. Certain antiretrovirals (ddI, ddC, d4T) are also known to cause neuropathy in this patient population. Therapeutic treatment of painful sensory neuropathy has been difficult. Current management involves the use of sympomatic or pain-modifying agents. Symptomatic relief with tricyclic antidepressants, non-steroidal anti-inflammatory agents, topical capsaicin or opiates has been limited. A trial is currently underway with a potentially restorative agent, nerve growth factor. Lamotrigine is a newly approved anti-convulsant which blocks voltage sensitive sodium channels, resulting in inhibition of glutamate and aspartate release. Lamotrigine has similar efficacy in maximal electro- shock models to carbamazepine and phenytoin, both of which have proven efficacious for the treatment of painful diabetic neuropathy. To date, there have only been anectodal reports of the efficacy of lamotrigine for treatment of HIV-associated sensory neuropathy.

Up to 15% of individuals infected with HIV infection develop marked cognitive and motor dysfunction, termed HIV-associated dementia. The introduction of highly active anti-retroviral therapy (HAART) has reduced deaths and the incidence of opportunistic infections, but therapeutic failures occur in about 50%. In many cases, therapeutic failures result from the acquisition of resistance mutations. The impact of HAART on the incidence or course of HIV dementia remains unclear, and the factors underlying variability in treatment response are uncertain. It is likely that durable suppression of CSF HIV levels will be determined by medication adherence and the prevention of anti-retroviral resistance. The CSF pharmacokinetics of anti-retroviral agents and the brain penetration of these agents will also be critical determinants of the successful suppression of CNS infection. Critical questions relating to the use of HAART in treating neurological disease include: first, does the development of anti-retroviral resistance among HIV quasi-species in CSF and brain tissue result in therapeutic failure? Second, do the CSF pharmacokinetics of anti-retrovirals predict therapeutic failure? Third, how does medication adherence, or compliance, influence the durable suppression of CSF HIV levels? All of these factors are potentially important elements of the successful treatment of CNS infection and HIV-D. We will determine the evolution of anti-retroviral resistance in plasma, CSF, and brain compartment in neurologically-characterized HIV-positive individuals initiation HAART. CSF HIV RNA levels will be measured to indicated the adequate long-term suppression of HIV, and related to the CSF pharmacokinetics of anti-retrovirals. Adherence with HAART will be measured using a unique, programmable, device prototype, and the factors influencing incomplete adherence will be studied. These studies will lead to an improved understanding of the relationship between resistance mutations and the durable suppression of CNS HIV infection. The observations relation to anti-retroviral pharmacokinetics and adherence of the CNS will have direct relevance for the design of improve therapies for the prevention and treatment of HIV dementia.

Evaluate the effect of rhNGF on epidermal nerve fiber density.

The purpose of this study is to determine the safety, tolerability and efficacy of pain relief of recombinant human nerve growth factor (rhNGF) for HIV-associated sensory neuropathy. Peripheral neuropathies are commonly seen in patients with HIV infection. Data from the Multi-center AIDS Cohort Study suggest that the incidence of sensory neuropathy is increasing rapidly. Autopsies have demonstrated evidence of peripheral nerve damage in 100% of patients dying from AIDS. Up to 30% of all patients with advanced HIV infection develop symptomatic peripheral neuropathy with pain, paresthesias and dyesthesias in the lower extremities. Although painful sensory neuropathy is not life threatening, it greatly affects the quality of life and adds significantly to the morbidity of HIV infection. The pathogenetic mechanisms underlying painful sensory neuropathy are not fully understood. It appears that macrophage- mediated infiltration of the peripheral nerve with local cytokine release and the development of length-dependent distal axonal degeneration is universal in patients with painful sensory neuropathy. Both large and small fibers are affected and show degeneration signs in a centripetal fashion. Until now, treatments have been symptomatic for HIV-associated sensory neuropathy, relying on pain modifying agents or membrane stabilizing drugs. Due to the prominence of the degeneration of the small nerve fibers which are known to be rhNGF-responsive, rhNGF is proposed as a specific restorative treatment for HIV-associated sensory neuropathy.

AIDS is associated with a marked cognitive and motor dysfunction, termed HIV-associated dementia, in up to 20% of individuals. The introduction of potent combination antiretroviral therapy has reduced deaths from AIDS, and improved immunodeficiency in many. However, the impact of these therapies on neurological disease has only been studied to a limited extent; and the incidence and progression of dementia among injection drug users remains uncertain. Less severe cognitive impairment, termed minor HIV-associated cognitive/motor disorder has been less extensively studied and its prognosis and progression remain undefined. The progression of HIV-associated dementia can be variable, and some patients have rapid progression after diagnosis of dementia. The determinants of this variability remain unknown, but if defined, might be modified to affect disease progression. The relationship between HIV-1 viral load in the peripheral compartment and the brain has not been explored with currently available sensitive assays of viral load. A number of critical questions relating to viral load remain unanswered. First, does increasing systemic viral burden in the later stages of HIV infection "drive" the development of neurologic disease. Second, is the amount of virus in the CSF reflective of virus production in the brain, or in the periphery?, and does it changes with antiretroviral therapy?. Finally, how is CNS immune activation, which is a critical component of CNS pathophysiology, related to blood and CSF viral load. We plan a systematic evaluation of virological and immunological markers in CSF in patients with HIV-associated cognitive/motor dysfunction to determine their utility as predictive markers for neurological disease progression. We have the following aims: 1) to determine the prognostic significance of CSF levels of HIV-1 RNA copy number for neurologic progression in a cohort of HIV-seropositive individuals; 2) to determine the dynamics of changes in HIV-1 RNA levels in plasma and CSF after initiation of combination antiretroviral therapy; 3) to determine the relationship between HIV RNA copy number in brain, plasma, and CSF and markers of immune activation. IF CSF HIV load measurement is validated as a predictive marker of neurological progression, individuals at high risk for neurological deterioration could be selected for aggressive neurologically-directed therapies.

Human immunodeficiency virus (HIV) is a virus that destroys the body's immune system. People infected with HIV can sometimes develop problems with memory, thinking and concentration. Individuals are invited to participate in this study testing the effect of CPI-1189 because they have HIV-related memory, thinking, concentration and motor problems. Antiretroviral agents are the only proven therapy for treating HIV thinking problems, but the treatment response is often poor. One reason for this poor response to antiretroviral agents may be that brain inflammation may be contributing to the dementia in addition to the brain virus infection. CPI-1189 is an experimental drug which may decrease inflammation in the brain. The trial will compare CPI-1189 to a placebo (an inactive substance similar to a sugar pill). This research study will examine how well people with HIV infection tolerate CPI-1189 and how safe this medicine is. The study will also see if there is any benefit of this drug on memory, thinking and concentration problems.

[unreadable] DESCRIPTION (provided by applicant): With recent declines in the incidence rates of HIV-associated dementia and CNS opportunistic infections, sensory neuropathies (HIV-SN) have become the commonest neurological disorders associated with AIDS. These include distal sensory polyneuropathy (DSP) and antiretroviral toxic neuropathy (ATN) and affect up to 30% of patients with advanced HIV disease. Pedal pain is prominent, but the underlying pathophysiological mechanisms remain undefined. There is limited information about the determinants and characteristics of sensory neuropathy related to ATN. Our underlying hypotheses are that: 1) the critical pathophysiological mechanisms underlying HIV-SN involve the over expression of specific chemokines and receptors. 2) The production of cytokines by macrophages in nerves drives uninjured C fiber coreceptors to spontaneous firing, leading to neuropathic pain. 3) The severity of neuropathic pain will be amplified by macrophage products in :nerves, and will correlate with circulating immune activation markers. 4) Neurotoxic antiretrovirals injure sensory nerve fibers through mitochondrial dysfunction, and neuropathic pain will correlate with levels of mitochondrial DNA. 5) Chemokine receptors on sensory neurons are involved in the induction of pain in HIV-SN. We will conduct a prospective study in a two parallel cohorts of adult HIV-infected patients. We will determine the incidence and prevalence of ATN, and delineate its pain characteristics, natural history, risk factors, predictive markers and mechanisms. Our long-term goal is to identify, prevent or treat HIV-SN. We will examine structural changes in epidermal nerves with skin biopsy, and functional changes in large and small caliber nerve fibers using quantitative sensory testing. Novel techniques developed by our collaborators at MU will be used to assess mitochondrial DNA levels after varying exposures to DDX agents. We will extend our studies of the immunopathology of HIV-SN, using our extensive tissue collections to define the relationship of chemokine upregulation to neuropathic pain.

AIDS /HIV neuropathy; pathologic process; nociceptors; neuropathology; neurotoxicology; C fiber; pain; mitochondrial DNA; cytokine; drug adverse effect; macrophage; antiviral agents; immunopathology; receptor expression; foot; neuroimmunomodulation; patient oriented research; clinical research; human subject;

AIDS /HIV neuropathy; HIV infections; drug adverse effect; pathologic process; AIDS therapy; antiviral agents; therapy adverse effect; neuropathology; functional ability; mental disorder diagnosis; combination chemotherapy; cooperative study; longitudinal human study; epidemiology; neuropsychology; substance abuse related disorder; patient oriented research; clinical research; human subject;

Abstract Not Provided:

nerve growth factors; AIDS /HIV neuropathy; human therapy evaluation; drug screening /evaluation; nervous system disorder chemotherapy; pain; injection /infusion; clinical trials; neuropharmacology; analgesia; patient oriented research; human subject; clinical research;

AIDS /HIV neuropathy; HIV infections; disease /disorder proneness /risk; pathologic process; virus load; helper T lymphocyte; antiviral agents; drug adverse effect; clinical research; human subject;

A. OBJECTIVES AND GOALS. The development and application of biomarkers in neurodegenerative diseases has become increasingly important to clinical practice, epidemiology and therapeutic trials. While substantial progress has been made at the basic science level in understanding the pathophysiology and development of animal models of HIV-D, there are significant limitations in our current ability to predict disease onset, to give definitive diagnoses, to measure disease progression and to detect accurately the effects of therapeutic intervention. Thus the development of objective biomarkers is critical to further our progress in this field. Realizing the potential importance of biomarkers, the Food and Drug Administration is making a major effort to bring biomarkers into the mainstream of drug discovery (1). The objectives of the Core are: 1. To assist in the development and monitoring of surrogate markers for HIV-D. 2. To provide mentorship and consultation for Neuro-AIDS researchers in the development of clinically useful surrogate markers for HIV-D and to validate these as associative, predictive markers, and as longitudinal markers of therapeutic effectiveness. This Core will interact extensively with the Clinical Outcomes Core (using the characterized samples derived from that Core), the Education and Skills Development Core (to disseminate information about the newly developed surrogate markers, and to assist with skill development in their application), and with the Therapeutics Core (to validate these markers in animal models). The statistical resources of the Clinical Outcomes Core will be essential for the interpretation of the clinical utility of markers derived from this core. Further details of the interactions are provided in individual Cores, and the overall Outline. This Core will provide a valuable resource to JHU investigators, and to the global Neuro-AIDS community. There is no similar systematic attempt to develop a series of clinically useful surrogate markers, so this Core will have a major impact on the field.

[unreadable] DESCRIPTION (provided by applicant): HIV-associated cognitive disorders remain prevalent, even among HIV positive individuals who receive highly active anti-retroviral treatments. There is a wealth of HIV-related neuroscience research at Johns Hopkins University (JHU), especially focused on oxidative stress as a critical pathogenic mechanism for neurological damage. Despite this rich environment, no definitive therapeutics for HIV-associated cognitive disorders have yet been developed. There is also an unfilled need to develop surrogate markers and more robust and simpler screening instruments for neurological diseases, which could eventually be used in resource-limited areas or by non-neurologists. Potential collaborations at Johns Hopkins are currently limited by the lack of a central organizing structure for this type of research and resources to facilitate cross-disciplinary and translational research. The JHU NIMH Center will address these needs to provide a resource to catalyze interdisciplinary research in HIV neuroscience. [unreadable] [unreadable] The goals of the JHU NIMH Center are to: 1. To facilitate collaborative research in HIV-related neuroscience with the goal of developing a definitive therapy for HIV-associated cognitive disorders based on targeting oxidative stress pathways. 2. To increase resources for HIV-related neuroscience research at JHU and to enhance the productivity of HIV-related neuroscience research locally, nationally and internationally. 3. To encourage high-risk, innovative developmental research in Neuro-AIDS, especially of a cross disciplinary nature. 4. To provide resources to encourage new investigators locally, nationally, and internationally to enter the field of HIV Neuro-AIDS research by providing educational and skill-developing resources for investigators to improve their expertise in detecting and treating HIV-related neurological complications. 5. To use focused throughput screening, using in vitro models to identify novel compounds useful for treatment of HIV-associated cognitive dysfunction with the over-arching theme of oxidative stress. 6. To identify and validate surrogate biomarkers based on proteomics and lipidomics[PSB1]. [unreadable] [unreadable] Administrative Core [unreadable] [unreadable] DESCRIPTION (provided by applicant): The overarching theme of the Center is the development of novel therapeutics for HIV-associated cognitive disorders and dementia. We have identified this as a high priority on the basis of our institutional strengths and continuing importance in clinical care. There is already a wealth of investigator-initiated HIV neuroscience research at Johns Hopkins University (JHU), especially focused on pathogenesis, as well as significant expertise in clinical trial design, and international work. Despite this rich environment, novel therapeutics for HIV-associated cognitive disorders have not entered clinical practice. Within the JHU HIV Neuroscience community, potential collaborations are limited by the lack of a central organizing structure, and specifically a facility to link different types of research, and to facilitate cross-disciplinary research. This Center will address these deficiencies. To achieve this goal, we propose to use the Center to bring together several HIV and simian immunodeficiency virus (SIV) neuroscience researchers at JHU, to work together on these goals. One of the strengths of the Center is that it builds on, and amplifies, the existing work in HIV-associated cognitive disorders and dementia (HIV-D), cognitive testing, clinical trials, therapeutic development and animal models of SIV encephalitis. All of this work is well established, but has not, to date, been fully integrated together. Newer areas of research, in the development of surrogate markers, in developing medication adherence markers, and in international work, will be added to bolster these aspects of interactive research. [unreadable] [unreadable] [unreadable] [PSB1]lipidomics?

B. Core Overview Funding for research in HIV-associated neurological disease at Johns Hopkins is substantial, spanning all aspects of Neuro-AIDS research, from behavioral interventions to molecular biology, pathogenesis and therapeutics. Despite the wealth of research and peer-reviewed NIH funding for studies of Neuro-AIDS, JHU investigators need a mechanism by which they can to pursue high-risk questions, develop new collaborations and pursue new areas of research that would lead to independent funding. This is especially relevant for therapeutically oriented research. In recent years, the JHU CFAR has provided pilot or developmental grants, but these are not solely focused on Neuro-AIDS; rather they are distributed across all content areas. Over the 5 years of CFAR pilots there have been 50 awards. Of these 8 (16%) were awarded to investigators studying HIV CNS disease. The CFAR model is, however, recognized as having been a very valuable and productive component of the CFAR's success, and we aim to emulate it in this Core. In addition, we anticipate that this Core will provide pilot grants to investigators outside JHU (who may have collaborations with JHU researchers), thus encouraging the entry of new investigators with new ideas into the field. This Developmental Core will provide critical seed money for such endeavors, and will thereby enhance the activities of the overall Center.

Acquired Immunodeficiency Syndrome; AIDS clinical trial group; AIDS Dementia Complex; Chairperson; Clinical; Clinical Trials; Cognition; Cognition Disorders; Data; Development; Epidemiologic Methods; Epidemiology; Goals; Grant; instrument; Laboratories; Measurement; medication compliance; Modality; Neurologic; Neurology; novel therapeutics; Outcome; Outcome Measure; Research; Research Infrastructure; Resources; Testing; Therapeutic Agents; treatment trial

Our proposal is strengthened by our previous extensive experience with the measurement of cognitive impairment in advanced HIV/AIDS, especially those with a history of substance abuse. The proposal builds on the established NEAD cohort already participating in longitudinal studies of HIV-1 infection in Baltimore. The specific aims are: AIM 1: To identify protein markers in CSF that can distinguish progressive from static HIV-associated neurocognitive disorders (HAND) in individuals with a history of substance abuse. Our hypothesis is that CSF protein markers will be able to differentiate the temporal progression of HAND, reflecting underlying pathophysiological processes, particularly the effects of oxidative stress. AIM 2: To identify protein markers in CSF that differentiate individuals who may be at high risk for the development of HAND because of an increased genetic vulnerability to oxidative stress. Our hypthesis is that CSF protein markers will show variability among individuals based on genetic differences in genes which may regulate host response to oxidative stress. This project relies on the careful, serial characterization of the neurocognitive status of individuals chronically infected with HIV-1. Detailed histories of substance abuse will be gathered so that we can fractionate the cohort by the patterns of drug use. We will also explore the role of genetic variability in the regulation of oxidative stress through our collaboration with Dr George Uhl, head of the Molecular Neurobiology group at NIDA. He has expertise in the areas of molecular neurobiology and complex genetics related to addiction

DESCRIPTION (provided by applicant): The SIV/Macaque Research Core will provide the expertise to evaluate novel therapeutics and surrogate markers in the era of highly active antiretroviral therapy (HAART) in a rigorous, validated animal model that recapitulates HIV CMS infection either in the absence or presence of HAART. Priority for testing will be based on how well the drug meets the established criteria. The Clinical Outcomes Core will be essential to translate novel therapeutics from the animal model into human clinical trials through it multiple connections to the Neuro-AIDS trial consortia. The SIV/Macaque Research Core will play a central role in the current JHU NIMH Center, and will interact with many of the other Cores. This Core will serve the following functions: 1) To evaluate candidate therapeutics identified in the Therapeutic Development Sub-Core or by investigators in the NIMH Center or external investigators in cultured primary macaque cells (lymphocytes, monocyte/macrophages, astrocytes and neural progenitor cells or neuroprogenitor-derived neurons) to determine whether it is appropriate to test the drugs in the SIV macaque model. 2) To provide the resources and expertise necessary to evaluate novel antioxidant/neuroprotective therapeutics in vivo in a rapid, validated SIV macaque model to provide "proof of concept" in vivo. The results of such studies will provide the scientific basis for larger studies in macaques (to delineate pathogenesis and mechanism, funded separately) and/or human clinical trials. 3) To collaborate with the Clinical Outcomes Core on novel therapeutics that show efficacy in the SIV/macaque model to initiate human clinical trials. 4) To collaborate with the Surrogate Marker Core on newly identified surrogate markers for HIV CNS disease, characterizing the pathological basis for the marker in the SIV/macaque model.

DESCRIPTION (provided by applicant): This new competing application requests support for establishment of an institutional NRSA in Neurological infectious Diseases at Johns Hopkins University. Neurological infections are a major cause of morbidity and mortality yet currently there are no other training programs in the country focused on neurological infections. We plan to develop a post-doctoral fellowship training program and will provide an exceptional training environment. Our training program is strengthened by the interaction of the following: an interdisciplinary approach to neurological infectious disease;focus on underserved populations, including those in resource limited countries;emphasis on scientific and methodological rigor in the design of patient-oriented or laboratory research;diverse opportunities to conduct ethically sound, community-based research both domestically and internationally;and broad clinical and research expertise in several different areas. We are requesting support for 2 post-doctoral slots during the first year of training, increasing thereafter to 3 post-doctoral slots. The trainees will pursue one of three tracks of training in neurological infections which includes laboratory based research, clinical and translational research or international research. Post-doctoral training will focus on mentored research, either in patient-oriented or laboratory areas, with a faculty advisor guiding research analysis, paper and grant writing. Our approach to training scientists for careers in Neurological Infectious Diseases will emphasize flexibility and a customized training program based on a core curriculum and the availability of the Graduate Training Program in Clinical Investigation. Training faculty has many years of experience with successful post-doctoral training and mentoring neurologists and other clinician-scientists. The success of our training program will be measured by research experiences, plus a wide array of studies and we anticipate that trainees from this program will compete successfully for KOS or K23 funding. These grant funds will provide a core of essential support for our Neurological Infectious Disease Research Training Program. This proposal will fulfill an important and critical need for training a future generation of clinician scientists RELEVANCE: The proposal will create a new training program for clinician scientists In neuro-infectious diseases. Neuroinfectlous diseases are a significant cause of morbidity, mortality and prolonged hospitalization. Yet, the eitiology and pathophysiology of many of these disaeses is poorly understood and no treatemtment is available. This program will be the first of its kind in the country devoted to training the next generation of researchers who specialize in these diseases.

DESCRIPTION (provided by applicant): This is a request for renewal of a previously funded R25 proposal to address issues of diversity in training of researchers in Neuro-AIDS and to train non-minority researchers in issues related to neuro-AIDS in minority populations. This started as a collaboration between Johns Hopkins University, University of Puerto Rico and University of Hawaii. Each of these institutions of their geographical location has a unique minority population. In the two and a half years since this grant was funded, we have exceeded all its original goals. We created a three part training program. A didactic session of 12 weeks, with another 6 career building lectures was taken by 88 researchers, 81% of whom are continuing a career in Neuro-AIDS. These lectures are state of the art with web-based design and strong participation from the trainees. They also include a journal club format to enhance discussion. Each of these lectures, address issues of diversity where relevant. The second part consists of research training with identification of appropriate mentors and projects. Several of the mentees have travelled to Baltimore to help establish collaborations and acquire research skills. The third part is the awarding of the pilot grants on a competitive basis to select individuals. These pilot grants have now been awarded twice to researchers from minority backgrounds. While too early to determine their long-term success, most have already generated data for abstracts and have generated preliminary data for NIH grant submission. Together the trainees that have published 56 manuscripts. Of the 59 trainees enrolled in years 1 and 2, nine received NIH grants. We have a detailed evaluation process of all aspects of the course and a strong outreach program to attract new researchers into the field. The demand for our course and participation in the research program has far exceeded our original expectations. Researchers in several institutions around the country expressed an interest. We now propose to expand the scope of this to meet these demands, although the major focus will continue to be on the three institutions mentioned above. We will also work with NIMH to help establish collaborations with the other R25 programs funded by them. PUBLIC HEALTH RELEVANCE: While the HIV epidemic has disproportionately affected minority populations in the US, very few minority researchers are engaged in neuro-AIDS research. The major goal of the proposal is to diversity the workforce and address research questions that specifically affect these populations and have not received adequate attention.

DESCRIPTION (provided by applicant): JHU NIMH Center for novel therapeutics for HIV-associated cognitive disorders. HIV-associated neurocognitive disorders (HAND) remain very prevalent, even among aviremic HIV+ individuals who treated with highly active antiretroviral treatments. HIV-related neuroscience research at Johns Hopkins University has focused on this challenging problem, exploring the issue of sustained CNS inflammation as a critical pathogenic mechanism for neurological damage. Despite the tremendous efforts to understand the mechanisms underlying the persistence of HAND, no definitive adjunctive therapeutics have yet entered clinical practice. There is also an unfilled need to develop surrogate markers and more robust and simpler screening instruments for HAND, to allow for earlier detection, for tracking of the course of HAND, and improving the efficiency of clinical trials. Collaborations at Johns Hopkins had been limited by the lack of a central organizing structure for this type of research, and resources to facilitate cross disciplinary and translational research. The JHU NIMH Center has addressed these needs over the past 5 years and has provided a resource to catalyze interdisciplinary research in HIV neuroscience, with the aim of leading to new therapies. The goals of the renewal application of the JHU NIMH Center are to: 1. To facilitate collaborative research in HIV-related neuroscience with the goal of developing a definitive therapy for HIV associated cognitive disorders based on targeting sustained CNS inflammation. 2. To increase resources for HIV-related neuroscience research at JHU and to enhance the productivity of HiV-related neuroscience research locally, nationally and internationally. 3. To encourage high-risk, innovative developmental research in Neuro-AIDS, especially of a cross-disciplinary nature with the specific aim of encouraging investigators (junior or senior) into this field. 4. To use focused medium throughput screening, using in vitro models to identify novel compounds useful for treatment of HIV-associated cognitive dysfunction with the over-arching theme of reducing the sustained CNS inflammation that we believe underlies the development of HAND. 5. To identify and validate surrogate biomarkers based on proteomics and lipomics.

DESCRIPTION (provided by applicant): The introduction of highly active antiretroviral therapy (HAART) for HIV/AIDS has improved survival. However, the prevalence of depression has not significantly changed. Depression is associated with poor clinical outcomes. A higher concentration of anti-HIV medication in the central nervous system (CNS) is hypothesized to be the primary modulator of beneficial neurological response. Several studies in medically related depressive disorders have suggested a role for inflammatory cytokines as provocateurs of depression. The recently described concept of CNS penetration effectiveness (CPE) scores of antiretroviral therapy (ART) allows improved estimation of concentration of antiretroviral (ARV) medication in the CNS whilst eliminating the challenge of obtaining CSF drug concentrations on each patient. Utilizing data from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort study, we propose to investigate if better CPE of ART reduces depression thereby resulting in better HIV clinical outcomes. We will assess the effect of CPE on adherence to ARV medication. We hypothesize that better CPE will be associated with improved mood and adherence. We also propose to evaluate changes in the inflammatory and trophic environment of the CNS and peripheral blood produced by the CPE of ART. We will assess the association between CPE of ART regimens and levels of CSF/blood pro-inflammatory cytokine mediators of depression, independent of viral load suppression. We hypothesize that increased CPE will decrease CSF and blood cytokines (Tumor Necrosis Factor-alpha, Interleukins-1, 6, and 12 and monocyte chemo attractant protein-1), thereby improving depression. We also seek to elucidate the association between depression and CSF virologic failure. This study will improve our understanding of the neuropathogenesis of HIV and the neurobehavioral effects of ARV treatment with respect to their CPE. This will help improve therapeutic choices for patients with HIV/AIDS and thereby improve clinical outcomes. An insight into changes in CSF/blood pro-inflammatory cytokines associated with the CPE of ART may be helpful in developing HIV treatments that have an additional effect of improving mood.

DESCRIPTION (provided by applicant): This new competing application requests support for establishment of an institutional NRSA in Neurological infectious Diseases at Johns Hopkins University. Neurological infections are a major cause of morbidity and mortality yet currently there are no other training programs in the country focused on neurological infections. We plan to develop a post-doctoral fellowship training program and will provide an exceptional training environment. Our training program is strengthened by the interaction of the following: an interdisciplinary approach to neurological infectious disease; focus on underserved populations, including those in resource limited countries; emphasis on scientific and methodological rigor in the design of patient-oriented or laboratory research; diverse opportunities to conduct ethically sound, community-based research both domestically and internationally; and broad clinical and research expertise in several different areas. We are requesting support for 2 post-doctoral slots during the first year of training, increasing thereafter to 3 post-doctoral slots. The trainees will pursue one of three tracks of training in neurological infections which includes laboratory based research, clinical and translational research or international research. Post-doctoral training will focus on mentored research, either in patient-oriented or laboratory areas, with a faculty advisor guiding research analysis, paper and grant writing. Our approach to training scientists for careers in Neurological Infectious Diseases will emphasize flexibility and a customized training program based on a core curriculum and the availability of the Graduate Training Program in Clinical Investigation. Training faculty has many years of experience with successful post-doctoral training and mentoring neurologists and other clinician-scientists. The success of our training program will be measured by research experiences, plus a wide array of studies and we anticipate that trainees from this program will compete successfully for KOS or K23 funding. These grant funds will provide a core of essential support for our Neurological Infectious Disease Research Training Program. This proposal will fulfill an important and critical need for training a future generation of clinician scientists RELEVANCE: The proposal will create a new training program for clinician scientists In neuro-infectious diseases. Neuroinfectlous diseases are a significant cause of morbidity, mortality and prolonged hospitalization. Yet, the eitiology and pathophysiology of many of these disaeses is poorly understood and no treatemtment is available. This program will be the first of its kind in the country devoted to training the next generation of researchers who specialize in these diseases.

? DESCRIPTION (provided by applicant): HIV-associated neurocognitive disorders (HAND) continue to be a remarkably prevalent condition in HIV- infected individuals despite the potent effects of combination antiretroviral therapy (cART). The development of HAND represents an important treatment issue for HIV patients that impacts quality of life, mortality, and everyday functioning. Currently, despite 25 years of research, no specific treatments have entered clinical practice for HAND. The overarching aim of this proposal is the development of a novel therapy, intranasal insulin, for HIV-associated neurocognitive disorders (HAND). We have identified this as an innovative, and high potential target based on our preliminary research. HIV-infection and cART are well known to cause alterations in lipid distribution, glucose homeostasis, and energy metabolism that are associated with alterations in insulin signaling. Several decades of research have shown that insulin has multiple actions in brain that regulate many of the same neural pathways perturbed by HIV infection including energy metabolism, lipid metabolism, neurotransmitter channel activity, neurite outgrowth, synaptic strength, and inflammatory signaling suggesting that insulin might protect the CNS in the setting of HIV-infection. In preliminary experiments we found that insulin protected neurons from a broad variety of insults including toxic HIV proteins, as well as ischemic, oxidative, inflammatory, and excitotoxic challenges, in addition to dampening the inflammatory response of microglia. In a novel animal model of HAND produced by infection of conventional mice with a chimeric HIV (EcoHIV) we found that intranasal insulin treatment for 9 days completely reversed cognitive impairment in infected animals. These data are consistent with human studies in healthy volunteers, Alzheimer's and type 2 diabetes patients showing that intranasal insulin improves cognitive function. These preliminary findings strongly suggest that insulin delivered directly to brain may preserve or restore neuronal function in HIV-infected individuals.

PROJECT SUMMARY ? OVERALL HIV-associated neurocognitive disorders (HAND) remain very prevalent, even among aviremic HIV+ individuals treated with CART. In the era of CART, the prevalence of HAND in HIV+ individuals with advanced infection remains around 40-50% [1, 2], and HAND may now be the most common form of young-age neurocognitive impairment globally [1]. Currently there are no uniformly accepted clinical, neuroimaging, or laboratory outcome measures for clinical trials for the treatment of HAND. HIV-related neuroscience research at Johns Hopkins University has focused on this challenging problem, exploring critical pathogenic mechanisms for neurological damage. Despite tremendous efforts to understand the mechanisms underlying the persistence of HAND, no definitive adjunctive therapeutics have yet entered clinical practice. There is also an unfilled need to develop surrogate markers and more robust and simpler screening instruments for HAND, to allow for earlier detection, for tracking of the course of HAND, and improving the efficiency of clinical trials. Until the NIMH Center was established at JHU collaborations had been limited by the lack of a central organizing structure for this type of research, and limited resources to facilitate cross-disciplinary and translational research. The JHU NIMH Center has addressed these needs over the past 11 years and has provided a resource to catalyze interdisciplinary research in HIV neuroscience, with the aim of leading to new therapies. Accomplishments of the Center are highlighted in the Overall Strategy section and in each individual core, and the key accomplishment is our proven ability to move HAND therapeutics from the discovery phase, through animal models, and on to clinical trials, with the ultimate goal of shifting clinical practice.